Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The eccentric cleavage product of ?-carotene, ?-apo-13-carotenone, functions as an antagonist of RXR?.

ABSTRACT: In this study, we investigated the effects of eccentric cleavage products of ?-carotene, i.e. ?-apocarotenoids (BACs), on retinoid X receptor alpha (RXR?) signaling. Transactivation assays were performed to test whether BACs activate or antagonize RXR?. Reporter gene constructs (RXRE-Luc, pRL-tk) and RXR? were transfected into Cos-1 cells and used to perform these assays. None of the BACs tested activated RXR?. Among the compounds tested, ?-apo-13-carotenone was found to antagonize the activation of RXR? by 9-cis-retinoic acid and was effective at concentrations as low as 1 nM. Molecular modeling studies revealed that ?-apo-13-carotenone makes molecular interactions like an antagonist of RXR?. The results suggest a possible function of BACs on RXR? signaling.

SUBMITTER: Eroglu A

PROVIDER: S-EPMC3517194 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The eccentric cleavage product of β-carotene, β-apo-13-carotenone, functions as an antagonist of RXRα.

Eroglu Abdulkerim A Hruszkewycz Damian P DP Curley Robert W RW Harrison Earl H EH

Archives of biochemistry and biophysics 20100801 1

In this study, we investigated the effects of eccentric cleavage products of β-carotene, i.e. β-apocarotenoids (BACs), on retinoid X receptor alpha (RXRα) signaling. Transactivation assays were performed to test whether BACs activate or antagonize RXRα. Reporter gene constructs (RXRE-Luc, pRL-tk) and RXRα were transfected into Cos-1 cells and used to perform these assays. None of the BACs tested activated RXRα. Among the compounds tested, β-apo-13-carotenone was found to antagonize the activatio ...[more]

PMID: 20678466

Similar Datasets

Naturally occurring eccentric cleavage products of provitamin A ?-carotene function as antagonists of retinoic acid receptors.

Project description:?-Carotene is the major dietary source of provitamin A. Central cleavage of ?-carotene catalyzed by ?-carotene oxygenase 1 yields two molecules of retinaldehyde. Subsequent oxidation produces all-trans-retinoic acid (ATRA), which functions as a ligand for a family of nuclear transcription factors, the retinoic acid receptors (RARs). Eccentric cleavage of ?-carotene at non-central double bonds is catalyzed by other enzymes and can also occur non-enzymatically. The products of these reactions are ?-apocarotenals and ?-apocarotenones, whose biological functions in mammals are unknown. We used reporter gene assays to show that none of the ?-apocarotenoids significantly activated RARs. Importantly, however, ?-apo-14'-carotenal, ?-apo-14'-carotenoic acid, and ?-apo-13-carotenone antagonized ATRA-induced transactivation of RARs. Competitive radioligand binding assays demonstrated that these putative RAR antagonists compete directly with retinoic acid for high affinity binding to purified receptors. Molecular modeling studies confirmed that ?-apo-13-carotenone can interact directly with the ligand binding site of the retinoid receptors. ?-Apo-13-carotenone and the ?-apo-14'-carotenoids inhibited ATRA-induced expression of retinoid responsive genes in Hep G2 cells. Finally, we developed an LC/MS method and found 3-5 nm ?-apo-13-carotenone was present in human plasma. These findings suggest that ?-apocarotenoids function as naturally occurring retinoid antagonists. The antagonism of retinoid signaling by these metabolites may have implications for the activities of dietary ?-carotene as a provitamin A and as a modulator of risk for cardiovascular disease and cancer.

| S-EPMC3346154 | biostudies-literature

Synthesis of apo-13- and apo-15-lycopenoids, cleavage products of lycopene that are retinoic acid antagonists.

Project description:Consumption of the tomato carotenoid, lycopene, has been associated with favorable health benefits. Some of lycopene's biological activity may be due to metabolites resulting from cleavage of the lycopene molecule. Because of their structural similarity to the retinoic acid receptor (RAR) antagonist, ?-apo-13-carotenone, the "first half" putative oxidative cleavage products of the symmetrical lycopene have been synthesized. All transformations proceed in moderate to good yield and some with high stereochemical integrity allowing ready access to these otherwise difficult to obtain terpenoids. In particular, the methods described allow ready access to the trans isomers of citral (geranial) and pseudoionone, important flavor and fragrance compounds that are not readily available isomerically pure and are building blocks for many of the longer apolycopenoids. In addition, all of the apo-11, apo-13, and apo-15 lycopenals/lycopenones/lycopenoic acids have been prepared. These compounds have been evaluated for their effect on RAR-induced genes in cultured hepatoma cells and, much like ?-apo-13-carotenone, the comparable apo-13-lycopenone and the apo-15-lycopenal behave as RAR antagonists. Furthermore, molecular modeling studies demonstrate that the apo-13-lycopenone efficiently docked into the ligand binding site of RAR?. Finally, isothermal titration calorimetry studies reveal that apo-13-lycopenone acts as an antagonist of RAR by inhibiting coactivator recruitment to the receptor.

| S-EPMC5408601 | biostudies-literature

β-Carotene and β-apo-8'-carotenal contents in processed foods in Korea.

Project description:A robust and rapid HPLC method for β-carotene and β-apo-8'-carotenal analyses in various processed foods was developed. The analysis method was validated for low-fat, moderate-fat, and high-fat food matrices. The two carotenoids were identified by LC-MS/MS. The detection limits for β-carotene and β-apo-8'-carotenal in the three food matrices were 0.08-0.27 µg/g and 0.09-0.18 µg/g, respectively. The inter- and intra-day accuracy and precision were in accordance with the Codex guidelines. The validated method was applied to 57 processed food samples, possibly containing β-carotene and β-apo-8'-carotenal, obtained in Korea. The detected β-carotene and β-apo-8'-carotenal levels in the samples ranged from not detected (ND) to 6.92 µg/g and ND to 1.63 µg/g, respectively. Chocolate and cheese samples had the highest β-carotene and β-apo-8'-carotenal levels, respectively. Notably, several samples with no labeled carotenoid additives contained β-carotene. Moreover, the developed analytical method was compatible with various processed food matrices.Supplementary informationThe online version contains supplementary material available at 10.1007/s10068-023-01285-2.

| S-EPMC10449700 | biostudies-literature

?-Carotene and its cleavage enzyme ?-carotene-15,15'-oxygenase (CMOI) affect retinoid metabolism in developing tissues.

Project description:The mammalian embryo relies on maternal circulating retinoids (vitamin A derivatives) for development. ?-Carotene is the major human dietary provitamin A. ?-Carotene-15,15'-oxygenase (CMOI) has been proposed as the main enzyme generating retinoid from ?-carotene in vivo. CMOI is expressed in embryonic tissues, suggesting that ?-carotene provides retinoids locally during development. We performed loss of CMOI function studies in mice lacking retinol-binding protein (RBP), an established model of embryonic vitamin A deficiency (VAD). We show that, unexpectedly, lack of CMOI in the developing tissues further exacerbates the severity of VAD and thus the embryonic malformations of RBP(-/-) mice. Since ?-carotene was not present in any of the mouse diets, we unveiled a novel action of CMOI independent from its ?-carotene cleavage activity. We also show for the first time that CMOI exerts an additional function on retinoid metabolism by influencing retinyl ester formation via modulation of lecithin:retinol acyltransferase (LRAT) activity, at least in developing tissues. Finally, we demonstrate unequivocally that ?-carotene can serve as an alternative vitamin A source for the in situ synthesis of retinoids in developing tissues by the action of CMOI.

| S-EPMC3079298 | biostudies-other

The unexpected teratogenicity of RXR antagonist UVI3003 via activation of PPAR? in Xenopus tropicalis.

Project description:The RXR agonist (triphenyltin, TPT) and the RXR antagonist (UVI3003) both show teratogenicity and, unexpectedly, induce similar malformations in Xenopus tropicalis embryos. In the present study, we exposed X. tropicalis embryos to UVI3003 in seven specific developmental windows and identified changes in gene expression. We further measured the ability of UVI3003 to activate Xenopus RXR? (xRXR?) and PPAR? (xPPAR?) in vitro and in vivo. We found that UVI3003 activated xPPAR? either in Cos7 cells (in vitro) or Xenopus embryos (in vivo). UVI3003 did not significantly activate human or mouse PPAR? in vitro; therefore, the activation of Xenopus PPAR? by UVI3003 is novel. The ability of UVI3003 to activate xPPAR? explains why UVI3003 and TPT yield similar phenotypes in Xenopus embryos. Our results indicate that activating PPAR? leads to teratogenic effects in Xenopus embryos. More generally, we infer that chemicals known to specifically modulate mammalian nuclear hormone receptors cannot be assumed to have the same activity in non-mammalian species, such as Xenopus. Rather they must be tested for activity and specificity on receptors of the species in question to avoid making inappropriate conclusions.

| S-EPMC5183475 | biostudies-other

Retinal accumulation of zeaxanthin, lutein, and ?-carotene in mice deficient in carotenoid cleavage enzymes.

Project description:Carotenoid supplementation can prevent and reduce the risk of age-related macular degeneration (AMD) and other ocular disease, but until now, there has been no validated and well-characterized mouse model which can be employed to investigate the protective mechanism and relevant metabolism of retinal carotenoids. ?-Carotene oxygenases 1 and 2 (BCO1 and BCO2) are the only two carotenoid cleavage enzymes found in animals. Mutations of the bco2 gene may cause accumulation of xanthophyll carotenoids in animal tissues, and BCO1 is involved in regulation of the intestinal absorption of carotenoids. To determine whether or not mice deficient in BCO1 and/or BCO2 can serve as a macular pigment mouse model, we investigated the retinal accumulation of carotenoids in these mice when fed with zeaxanthin, lutein, or ?-carotene using an optimized carotenoid feeding method. HPLC analysis revealed that all three carotenoids were detected in sera, livers, retinal pigment epithelium (RPE)/choroids, and retinas of all of the mice, except that no carotenoid was detectable in the retinas of wild type (WT) mice. Significantly higher amounts of zeaxanthin and lutein accumulated in the retinas of BCO2 knockout (bco2-/-) mice and BCO1/BCO2 double knockout (bco1-/-/bco2-/-) mice relative to BCO1 knockout (bco1-/-) mice, while bco1-/- mice preferred to take up ?-carotene. The levels of zeaxanthin and lutein were higher than ?-carotene levels in the bco1-/-/bco2-/- retina, consistent with preferential uptake of xanthophyll carotenoids by retina. Oxidative metabolites were detected in mice fed with lutein or zeaxanthin but not in mice fed with ?-carotene. These results indicate that bco2-/- and bco1-/-/bco2-/- mice could serve as reasonable non-primate models for macular pigment function in the vertebrate eye, while bco1-/- mice may be more useful for studies related to ?-carotene.

| S-EPMC5494257 | biostudies-literature

Discovery of a Potent Retinoid X Receptor Antagonist Structurally Closely Related to RXR Agonist NEt-3IB.

Project description:We discovered a potent retinoid X receptor (RXR) antagonist, 6-[N-ethyl-N-(5-isobutoxy-4-isopropyl-2-(E)-styrylphenyl)amino]nicotinic acid (13e), that is structurally closely related to the RXR full agonist 6-[N-ethyl-N-(3-isobutoxy-4-isopropylphenyl)amino]nicotinic acid (NEt-3IB) (4). Compound 13e was synthesized via a simple route from 11, a methyl ester precursor of 4. Because 11 possesses high electrophilic reactivity because of the amino and alkoxy groups, it was readily transformed to 12 by iodization, and the iodine atom of 12 was converted to a C-C or C-N bond by means of palladium-catalyzed reaction to afford 13. Transcriptional activation assay revealed that 13g (in which the iodine atom was replaced with an amino group) is a weak RXR agonist, while 13d (a phenyl group), 13e (a styryl group), and 13f (an anilino group) are RXR antagonists. Among them, 13e was found to be more potent than the known RXR antagonist PA452 (9).

| S-EPMC4018080 | biostudies-literature

Enzymatic formation of apo-carotenoids from the xanthophyll carotenoids lutein, zeaxanthin and β-cryptoxanthin by ferret carotene-9',10'-monooxygenase.

Project description:Xanthophyll carotenoids, such as lutein, zeaxanthin and β-cryptoxanthin, may provide potential health benefits against chronic and degenerative diseases. Investigating pathways of xanthophyll metabolism are important to understanding their biological functions. Carotene-15,15'-monooxygenase (CMO1) has been shown to be involved in vitamin A formation, while recent studies suggest that carotene-9',10'-monooxygenase (CMO2) may have a broader substrate specificity than previously recognized. In this in vitro study, we investigated baculovirus-generated recombinant ferret CMO2 cleavage activity towards the carotenoid substrates zeaxanthin, lutein and β-cryptoxanthin. Utilizing HPLC, LC-MS and GC-MS, we identified both volatile and non-volatile apo-carotenoid products including 3-OH-β-ionone, 3-OH-α-ionone, β-ionone, 3-OH-α-apo-10'-carotenal, 3-OH-β-apo-10'-carotenal, and β-apo-10'-carotenal, indicating cleavage at both the 9,10 and 9',10' carbon-carbon double bond. Enzyme kinetic analysis indicated the xanthophylls zeaxanthin and lutein are preferentially cleaved over β-cryptoxanthin, indicating a key role of CMO2 in non-provitamin A carotenoid metabolism. Furthermore, incubation of 3-OH-β-apo-10'-carotenal with CMO2 lysate resulted in the formation of 3-OH-β-ionone. In the presence of NAD(+), in vitro incubation of 3-OH-β-apo-10'-carotenal with ferret hepatic homogenates formed 3-OH-β-apo-10'-carotenoic acid. Since apo-carotenoids serve as important signaling molecules in a variety of biological processes, enzymatic cleavage of xanthophylls by mammalian CMO2 represents a new avenue of research regarding vertebrate carotenoid metabolism and biological function.

| S-EPMC3026080 | biostudies-literature

RXR gamma null mice are apparently normal and compound RXR alpha +/-/RXR beta -/-/RXR gamma -/- mutant mice are viable.

Project description:The RXR gamma (RXR, retinoid X receptor) gene was disrupted in the mouse. Homozygous mutant mice developed normally and were indistinguishable from their RXR gamma +/- or wild-type littermates with respect to growth, fertility, viability, and apparent behavior in the animal facility. Moreover, RXR alpha -/-/RXR gamma -/- and RXR beta -/-/RXR gamma -/- mutant phenotypes were indistinguishable from those of RXR alpha -/- and RXR beta -/- mutants, respectively. Strikingly, RXR alpha +/-/RXR beta -/-/RXR gamma -/- triple mutants were viable. Thus, it appears that RXR gamma does not exert any essential function that cannot be performed by RXR alpha or RXR beta, and one copy of RXR alpha is sufficient to perform most of the functions of the RXRs.

| S-EPMC38586 | biostudies-other

Force-induced cleavage of single VWFA1A2A3 tridomains by ADAMTS-13.

Project description:A disintegrin and metalloprotease with a thrombospondin type 1 motifs 13 (ADAMTS-13) regulates hemostasis by cleaving the folded A2 domain of von Willebrand factor (VWF). The cleavage is regulated by forces as it occurs in flowing blood. We tested the hypothesis that force-induced A2 domain unfolding facilitates cleavage using atomic force microscopy to pull single VWF A1A2A3 tridomain polypeptides by platelet glycoprotein Ibalpha or antibodies to measure time, distance, and force. Structural destabilization of A1A2A3 was induced by 5- to 80-pN forces, manifesting as an abrupt molecular length increase distributed around 20 and 50 nm, probably because of uncoupling A1A2A3 (or partially unfolding A2) and fully unfolding A2, respectively. Time required to destabilize A1A2A3 first increased (catch), reaching a maximum of 0.2 seconds at 20pN, then decreased (slip) with increasing force, independent of ADAMTS-13. The time required to rupture A1A2A3 exhibited a similar catch-slip behavior when pulled by glycoprotein Ibalpha but only slip behavior when pulled by antibody, which was progressively shortened by increasing concentration of ADAMTS-13 after (but not before) structural destabilization, indicating that cleavage of A2 requires the force-induced A2 unfolding. Analysis with a model for single-substrate trimolecular enzymatic kinetics estimated a cleavage rate k(cat) of 2.9 (+/- 59) seconds and a K(d) of 5.6 (+/- 3.4) nM for ADAMTS-13/A1A2A3 binding. These findings quantify the mechanical regulation of VWF cleavage by ADAMTS-13 at the level of single A1A2A3 tridomain.

| S-EPMC2808159 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data